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    Pyrazole inhibitors of COX-2 and sEH
    5.
    发明授权
    Pyrazole inhibitors of COX-2 and sEH 有权
    吡唑类抑制剂COX-2和sEH

    公开(公告)号：US09096532B2

    公开(公告)日：2015-08-04

    申请号：US13993317

    申请日：2011-12-12

    申请人： Bruce D. Hammock ,  Sung Hee Hwang ,  Karen Wagner ,  Christophe Morisseau ,  Aaron Wecksler ,  Guodong Zhang

    发明人： Bruce D. Hammock ,  Sung Hee Hwang ,  Karen Wagner ,  Christophe Morisseau ,  Aaron Wecksler ,  Guodong Zhang

    IPC分类号： A61K31/635 ,  C07D231/10 ,  C07D231/12 ,  C07D231/40 ,  C07D231/14

    CPC分类号： C07D231/12 ,  C07D231/14 ,  C07D231/40

    摘要： The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

    摘要翻译： 本发明提供化合物和组合物，例如一系列化合物，其中1,5-双芳基吡唑基团可通过不可裂解的共价链与脲基团缀合，其可用作双重COX-2 / sEH抑制剂。 本文公开的化合物具有与花生四烯酸级联相关的活性。 使用脂多糖（LPS）诱导的大鼠疼痛模型证明了这些化合物的活性。 与相同剂量的塞来昔布（即，COX-2抑制剂）相比，本发明的化合物与同样剂量的t-AUCB（即sEH抑制剂）相比，表现出优异的抗异常性疼痛活性，并且还作为 与联合给药相同剂量的塞来昔布和t-AUCB相比。 本发明的双重抑制剂在伤害性行为测定中表现出增强的体内抗异常性疼痛活性。 此外，本发明的化合物还证明对体内，体内和体内对内皮细胞（HUVEC）具有有效的抗血管生成作用并抑制血管生成。 本发明的双重抑制剂还表现出对血管内肿瘤生长缓慢的抗血管生成作用。

    PYRAZOLE INHIBITORS OF COX-2 AND SEH
    7.
    发明申请
    PYRAZOLE INHIBITORS OF COX-2 AND SEH 有权
    COX-2和SEH的吡唑抑制剂

    公开(公告)号：US20140038923A1

    公开(公告)日：2014-02-06

    申请号：US13993317

    申请日：2011-12-12

    申请人： Bruce D. Hammock ,  Sung Hee Hwang ,  Karen Wagner ,  Christophe Morisseau ,  Aaron Wecksler ,  Guodong Zhang

    发明人： Bruce D. Hammock ,  Sung Hee Hwang ,  Karen Wagner ,  Christophe Morisseau ,  Aaron Wecksler ,  Guodong Zhang

    IPC分类号： C07D231/12 ,  C07D231/14

    CPC分类号： C07D231/12 ,  C07D231/14 ,  C07D231/40

    摘要： The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

    摘要翻译： 本发明提供化合物和组合物，例如一系列化合物，其中1,5-双芳基吡唑基团可通过不可裂解的共价链与脲基团缀合，其可用作双重COX-2 / sEH抑制剂。 本文公开的化合物具有与花生四烯酸级联相关的活性。 使用脂多糖（LPS）诱导的大鼠疼痛模型证明了这些化合物的活性。 与相同剂量的塞来昔布（即，COX-2抑制剂）相比，本发明的化合物与同样剂量的t-AUCB（即sEH抑制剂）相比，表现出优异的抗异常性疼痛活性，并且还作为 与联合给药相同剂量的塞来昔布和t-AUCB相比。 本发明的双重抑制剂在伤害性行为测定中表现出增强的体内抗异常性疼痛活性。 此外，本发明的化合物还证明对体内，体内和体内对内皮细胞（HUVEC）具有有效的抗血管生成作用并抑制血管生成。 本发明的双重抑制剂还表现出对血管内肿瘤生长缓慢的抗血管生成作用。

    INHIBITORS OF EPOXIDE HYDROLASES FOR THE TREATMENT OF HYPERTENSION
    8.
    发明申请
    INHIBITORS OF EPOXIDE HYDROLASES FOR THE TREATMENT OF HYPERTENSION 审中-公开
    用于治疗高血压的环氧化物水解物的抑制剂

    公开(公告)号：US20110245331A1

    公开(公告)日：2011-10-06

    申请号：US13113028

    申请日：2011-05-20

    申请人： Deanna L. Kroetz ,  Darryl C. Zeldin ,  Bruce D. Hammock ,  Christophe Morisseau

    发明人： Deanna L. Kroetz ,  Darryl C. Zeldin ,  Bruce D. Hammock ,  Christophe Morisseau

    IPC分类号： A61K31/7088 ,  A61P9/12 ,  C12N9/96 ,  C12Q1/34

    CPC分类号： A61K31/325 ,  A61K31/00 ,  A61K31/336

    摘要： The invention provides compounds that inhibit epoxide hydrolase in therapeutic applications for treating hypertension. A preferred class of compounds for practicing the invention have the structure shown by Formula 1 wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R1-R4 is hydrogen, R2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R1 and R3 is each independently C1-C20 substituted or unsubstituted alkyl, cycloalkyl, aryl, acyl, or heterocyclic.

    摘要翻译： 本发明提供在治疗高血压的治疗应用中抑制环氧化物水解酶的化合物。 用于实施本发明的一类优选的化合物具有式1所示的结构，其中Z是氧或硫，W是碳磷或硫，X和Y各自独立地是氮，氧或硫，并且X还可以是碳， 当X为氮时，R 1为R 4为氢，R 2为氢时，当X为硫或氧时不存在，当Y为氮时为R4，当Y为硫或氧时不存在，R 1和R 3为 各自独立地为C1-C20取代或未取代的烷基，环烷基，芳基，酰基或杂环。